Pulmonary arterial hypertension (PAH) is a clinical hemodynamic syndrome characterized by elevated pulmonary arterial pressure and pulmonary vascular resistance leading to right heart failure and death. Vascular remodeling is the most prominent histopathological feature of PAH, which is regulated by many factors. Endoplasmic reticulum stress, calcium disorder and mitochondrial dysfunction are involved in the vascular cell proliferation and apoptosis by regulating intracellular calcium homeostasis and cellular metabolism. Epigenetic phenomenon such as DNA damage and abnormal expression of miRNA are also involved in the regulation of abnormal proliferation of vascular cells. Vascular cell phenotype switching including endothelial-mesenchymal transition and smooth muscle cell phenotype switching play an important role in abnormal proliferation of vascular cells. Vascular remodeling is produced by a variety of cells and molecular pathways, and aiming at multiple targets which is expected to find a new breakthrough in the treatment of PAH,and to improve abnormal vascular remodeling, delay or even reverse the progression of PAH.
Cell Proliferation ; Cells, Cultured ; Humans ; Hypertension, Pulmonary ; physiopathology ; MicroRNAs ; genetics ; Myocytes, Smooth Muscle ; pathology ; Pulmonary Artery ; pathology ; Vascular Remodeling ; genetics

OBJECTIVE: To investigate the effects of apple polyphenols on pulmonary vascular remodeling in rats with pulmonary arterial hypertension and its mechanism. METHODS: Rats were randomly divided into 4 groups:control (Con) group, monocrotaline (MCT) group, apple polyphenol (APP) group,monocrotaline + apple polyphenol (MCT+APP) group. In Con group, rats received a subcutaneous injection of physical saline. In APP group, rats received intraperitoneal injection of 20 mg/kg APP, every other day. In MCT group, rats received a single subcutaneous injection of MCT(60 mg/kg). In MCT+APP group, rats received subcutaneous injection of 60 mg/kg MCT followed by an intraperitoneal injection of 20 mg/kg APP every other day. All the disposal lasted 3 weeks. Then the PAH-relevant indicators, such as mean pulmonary artery pressure(mPAP), pulmonary vascular resistance(PVR), right ventricular hypertrophy index (RVHI) ,wall thickness (WT%) and wall area (WA%) were tested. After that, the inflammatory pathway related indicators, such as interleukin1(IL-1),interleukin1(IL-6), tumor necrosis factor α(TNF-α), cyclooxygenase 2(COX-2) and myeloperoxidase(MPO) in pulmonary tissue and free intracellular Ca in pulmonary smooth muscle cell(PASMC), content of eNOS and NO in endothelial cells were determined. RESULTS: Compared with the control group, the levels of mPAP, PVR, RVHI, WA%, WT%, and IL-1, IL-6, TNF-α, COX-2, MPO in tissue and the expression of Ca in PASMC of MCT group were increased significantly, while the contents of eNOS and NO in endothelial cells were decreased significantly (P＜0.05). Compared with the MCT group, the apple polyphenol treatment could improve the above mentioned situation, and the COX-2 and Ca indicators of the apple polyphenol treatment group were decreased significantly (P＜0.05). CONCLUSION MCT can increase COX-2 expression and intracellular Ca in pulmonary artery smooth muscle cells, decrease the contents of eNOS and NO in endothelial cells, while apple polyphenols can significantly inhibit these effects.
Animals ; Calcium ; metabolism ; Cyclooxygenase 2 ; metabolism ; Cytokines ; metabolism ; Malus ; chemistry ; Monocrotaline ; Nitric Oxide ; metabolism ; Nitric Oxide Synthase Type III ; metabolism ; Polyphenols ; pharmacology ; Pulmonary Artery ; drug effects ; pathology ; Random Allocation ; Rats ; Vascular Remodeling ; drug effects

BACKGROUND AND OBJECTIVES: Macitentan (MAC) reduces morbidity and mortality among advanced-stage pulmonary arterial hypertension (PAH) patients. However, data regarding the histopathologic and hemodynamic benefits of MAC treatment at an early stage of PAH is lacking. METHODS: One week after monocrotaline (MCT) injection, rats were randomly assigned to MAC (n=16), MAC combined with sildenafil (SIL) (MAC+SIL, n=16), or normal saline (MCT, n=16). Twelve sham rats (Sham) were included for comparison. Right ventricular (RV) systolic function was assessed via echocardiography as the RV fractional area change (RV-FAC). An invasive pressure-volume analysis using a Millar conductance catheter was performed 7 weeks after MCT injection. Rats were subsequently euthanized for histopathologic analysis. RESULTS: RV-right atrial pressure gradient on echocardiography was significantly increased 3 weeks after MCT injection, but was maintained in the Sham. RV-FAC was less deteriorated in the MAC, compared to that in the MCT (44±3% vs. 25±7%, p < 0.05), and the co-administration of SIL showed no additional benefit (45±8%, p > 0.05 vs. the MAC). On invasive hemodynamic analyses, RV end-systolic (196±78 µL) and end-diastolic volumes (310±86 µL), pulmonary artery systolic pressure (89±7.2 mmHg), and end-systolic pressure-volume relationship (−254±25.1) were significantly worse in the MCT vs. in the MAC (101±45 µL, 235±55 µL, 40±10.5 mmHg, and −145±42.1, respectively) and MAC+SIL (109±47 µL, 242±46 µL, 38±9.2 mmHg, and −151±39.2, respectively) (all p < 0.05). However, the MAC and MAC+SIL did not differ (all p > 0.05). On histopathology, both RV and lung fibrosis were significantly reduced in the MAC and MAC+SIL vs. in the MCT (all p < 0.05); the 2 treatment groups did not differ. CONCLUSIONS: MAC treatment at an earlier stage significantly attenuated experimental PAH progression hemodynamically and histopathologically.
Animals ; Atrial Pressure ; Blood Pressure ; Catheters ; Echocardiography ; Fibrosis ; Hemodynamics ; Humans ; Hypertension ; Hypertension, Pulmonary ; Lung ; Models, Animal ; Monocrotaline ; Mortality ; Pathology ; Pulmonary Artery ; Rats ; Sildenafil Citrate

OBJECTIVETo study the effect of calcium-sensing receptor (CaSR) agonists and antagonists on the expression of CaSR in neonatal mice with persistent pulmonary hypertension (PPHN), and to clarify the role of CaSR in neonatal mice with PPHN.

METHODSForty-nine neonatal mice were randomly divided into four groups: control (n=10), hypoxia (PPHN; n=11), agonist (n=13), and antagonist (n=15). The mice in the PPHN, agonist, and antagonist groups were exposed to an oxygen concentration of 12%, and those in the control group were exposed to the air. The mice in the agonist and antagonist groups were intraperitoneally injected with gadolinium chloride (16 mg/kg) and NPS2390 (1 mg/kg) respectively once daily. Those in the PPHN and the control groups were given normal saline daily. All the mice were treated for 14 consecutive days. Hematoxylin and eosin staining and immunohistochemistry were used to observe the changes in pulmonary vessels. Laser confocal microscopy was used to observe the site of CaSR expression and measure its content in lung tissues. qRT-PCR and Western blot were used to measure the mRNA and protein expression of CaSR in lung tissues.

RESULTSCompared with the control group, the PPHN group had significant increases in the pulmonary small artery wall thickness and the ratio of right to left ventricular wall thickness (P<0.05), which suggested that the model was successfully prepared. Compared with the control group, the PPHN group had a significant increase in the mRNA and protein expression of CaSR (P<0.05), and the agonist group had a significantly greater increase (P<0.05); the antagonist group had a significant reduction in the mRNA and protein expression of CaSR (P<0.05).

CONCLUSIONSCaSR may play an important role in the development of PPHN induced by hypoxia in neonatal mice.

Animals ; Hypoxia ; complications ; Lung ; pathology ; Mice ; Myocardium ; pathology ; Persistent Fetal Circulation Syndrome ; etiology ; pathology ; Pulmonary Artery ; pathology ; RNA, Messenger ; analysis ; Receptors, Calcium-Sensing ; analysis ; genetics ; physiology

OBJECTIVETo investigate the protective effect of heat shock protein 70 (HSP70) against hypoxic pulmonary hypertension (HPH) in neonatal rats.

METHODSA total of 128 neonatal rats were randomly divided into blank control group, HPH model group, empty virus group, and HSP70 group, with 32 rats in each group. Before the establishment of an HPH model, the rats in the blank control group and HPH model group were given caudal vein injection of 5 μL sterile saline, those in the empty virus group were given caudal vein injection of 5 μL Ad-GFP (1 010 PFU/mL), and those in the HSP70 group were given caudal vein injection of 5 μL Ad-HSP70 (1 010 PFU/mL). HPH model was prepared in the HPH model, empty virus, and HSP70 groups after transfection. At 3, 7, 10, and 14 days after model establishment, a multi-channel physiological recorder was used to record mean pulmonary arterial pressure (mPAP), optical and electron microscopes were used to observe the structure and remodeling parameters of pulmonary vessels, and Western blot was used to measure the protein expression of HSP70, hypoxia-inducible factor-1α (HIF-1α), endothelin-1 (ET-1), and inducible nitric oxide synthase (iNOS) in lung tissues.

RESULTSAt 3, 7, 10, and 14 days after model establishment, the HPH model group and the empty virus group had a significantly higher mPAP than the blank control group (P<0.05). On days 7 and 10 of hypoxia, the blank control group and the HSP70 group had significantly lower MA% and MT% than the HPH model group and the empty virus group (P<0.01); on day 14 of hypoxia, the HPH model group, empty virus group, and HSP70 group had similar MA% and MT% (P>0.05), but had significantly higher MA% and MT% than the blank control group (P<0.01). On days 3, 7 and 10 of hypoxia, the HSP70 group had significantly higher protein expression of HSP70 than the HPH model group, empty virus group, and blank control group (P<0.01); the HSP70 group had significantly lower expression of HIF-1α, ET-1, and iNOS than the HPH model group and the empty virus group (P<0.05) and similar expression of HIF-1α, ET-1, and iNOS as the blank control group (P>0.05).

CONCLUSIONSIn neonatal rats with HPH, HSP70 transfection can increase the expression of HSP70 in lung tissues, downregulate the expression of HIF-1α, ET-1, and iNOS, alleviate pulmonary vascular remodeling, and reduce pulmonary artery pressure; therefore, it may become a new strategy for the treatment of HPH in neonates.

Animals ; Disease Models, Animal ; Endothelin-1 ; analysis ; HSP70 Heat-Shock Proteins ; genetics ; physiology ; Hypertension, Pulmonary ; prevention & control ; Hypoxia ; complications ; Hypoxia-Inducible Factor 1, alpha Subunit ; analysis ; Nitric Oxide Synthase Type II ; analysis ; Pulmonary Artery ; pathology ; Rats ; Rats, Wistar ; Transfection

Tetralogy of Fallot (TOF) is one of the most common forms of cyanotic congenital heart disease usually managed by serial surgical repairs. The repaired prosthetic valve or conduit is susceptible to life-threatening infection. FDG-PET is an effective alternative to evaluate the source of infection when other examinations are inconclusive. We report an unusual case of an infected pulmonary artery conduit after TOF repair although the echocardiogram was negative for vegetation, which was later confirmed by surgery and pathology. The case highlights the role of FDG-PETas a problem-solving tool for potential endocarditis and cardiac device infection cases after complex cardiac surgery.
Endocarditis ; Heart Defects, Congenital ; Pathology ; Pulmonary Artery ; Tetralogy of Fallot ; Thoracic Surgery

Adult ; Aged ; Biopsy ; methods ; Female ; Humans ; Male ; Middle Aged ; Pulmonary Artery ; pathology ; Sarcoma ; diagnosis ; Vascular Neoplasms ; diagnosis

To investigate the effects and the underlying molecular mechanisms of curcumin on pulmonary artery smooth muscle cells in rat model with chronic obstructive pulmonary disease (COPD).A total of 75 male Wistar rats were randomly divided into control group (group CN), model group (group M), low-dose curcumin group (group CL), medium-dose curcumin group (group CM) and high-dose curcumin group (group CH). HE staining was used to observe the morphology of pulmonary artery. Proliferating cell nuclear antigen (PCNA), apoptosis-related protein Bcl-2 and Bax were detected by immunohistochemical staining. TUNEL kit was used to analyze the effects of curcumin on apoptosis of smooth muscle cells, and the protein expressions of SOCS-3/JAK2/STAT pathway in lung tissues were determined by western blot.Right ventricular systolic pressure (RVSP) and right ventricular hypertrophy index (RVMI) in group M were significantly higher than those in group CN, group CH and group CM (all<0.05). HE staining and TUNEL kit test showed that the number of pulmonary artery smooth muscle cells had a significant increase in group M, while the pulmonary artery tube became thin, and the smooth muscle cells shrinked in group CM and group CH. Immunohistochemistry showed that PCNA and Bcl-2 in group M were significantly higher than those in group CN (all<0.05), while Bax expression was significantly lower than that in group CN (<0.05). PCNA in group CM and group CH were significantly lower than that in group M (all<0.05), while Bax expression was significantly higher than that in group M (<0.05). Western blot showed that SOCS-3 protein was significantly decreased in group M, while the p-JAK2, p-STAT1, p-STAT3 were significantly increased (all<0.05). Compared with group M, SOCS-3 protein in group CM and group CH were significantly increased (all<0.05), while the p-JAK2, p-STAT3 were significantly reduced (all<0.05).Curcumin could promote the apoptosis of smooth muscle cells in rats with COPD, and improve the mean pulmonary artery pressure and RVMI through stimulating SOCS-3/JAK2/STAT signaling pathway.
Animals ; Apoptosis ; drug effects ; physiology ; Arterial Pressure ; drug effects ; physiology ; Curcumin ; pharmacology ; Hypertrophy, Right Ventricular ; pathology ; physiopathology ; Janus Kinase 2 ; drug effects ; physiology ; Lung ; chemistry ; drug effects ; Male ; Myocytes, Smooth Muscle ; drug effects ; pathology ; Proliferating Cell Nuclear Antigen ; drug effects ; metabolism ; Proto-Oncogene Proteins c-bcl-2 ; drug effects ; metabolism ; Pulmonary Artery ; drug effects ; pathology ; Pulmonary Disease, Chronic Obstructive ; pathology ; physiopathology ; Rats ; Rats, Wistar ; STAT Transcription Factors ; Suppressor of Cytokine Signaling 3 Protein ; drug effects ; physiology ; Ventricular Pressure ; drug effects ; bcl-2-Associated X Protein ; drug effects ; metabolism

We presented a rare case of a 64-year-old man with a combined anomaly of the bronchus and pulmonary artery that was detected incidentally. Computed tomography showed a hyperlucent, aerated sequestered segment of the right lower lung with an independent ectopic bronchus, which had no connection to the other airway. The affected segment was supplied by its own aberrant pulmonary artery branch from the right pulmonary trunk. This anomaly cannot be classified with any of the previously reported anomalies.
Bronchi/pathology ; Bronchopulmonary Sequestration/*radiography ; Humans ; Lung/*radiography ; Male ; Middle Aged ; Pulmonary Artery/*radiography ; Tomography, X-Ray Computed

Coronary Angiography ; Coronary Vessel Anomalies ; diagnosis ; Humans ; Pulmonary Artery ; pathology